Steroidal 3-keto-delta 1 4-diene-3-enamines

ABSTRACT

THIS INVENTION RELATES TO THE SYNTHESIS OF STERODIAL 3-KETO$184-DIENE 3-ENAMINESUSING TITANIUM TETARACHLORIDE AS AN ASSISTANT TO THE REACTION.

United States Patent O 3,629,298 STEROIDAL 3-KETO-A -DlENE-C'a-ENAMlNES Verlan H. Van Rheeneu, Kalamazoo, MiclL, assignor to The Upiohn Company, Kalamazoo, Mich.

No Drawing. Continuation-impart of application Ser. No. 643,825, June 6, 1967. This application Feb. 24, 1969, Ser. No. 801,859

Int. Cl. C07c 169/24 U.S. Cl. Mil-397.1 6 Claims ABSTRACT OF THE DISCLOSURE This invention relates to the synthesis of steroidal 3-keto- A -diene 3-enamines using titanium tetarachloride as an assistant to the reaction.

REFERENCE TO RELATED APPLICATION This is a continuation-in-part of application Ser. No. 643,825, filed June 6, 1967 now abandoned.

SUMMARY OF THE INVENTION According to the invention, steroidal 3-keto-A -dienes possessing a double bond at C such as the 3-keto-1,4,17 (20)-pregnatrien-21-carbonyloxyl steroids disclosed in U.S. Patent 2,774,775, can be converted to the B-enamines by reaction with a secondary amine such as dimethylamine, diethylamine or pyrrolidine in the presence of titanium tetrachloride and, preferably, in an inert organic solvent such as benzene.

The 3-enamines of 3-keto-A -steroid dienes that are prepared in accordance with this invention are useful chemical intermediates for the synthesis of biologically active steroids as disclosed in the patent identified above, the function of the 3-enamine group being to protect the A-ring functionality from chemical reaction such as reduction, while carrying on reductive reactions at other positions in the molecule, e.g., at an ll-keto group or a 21-carboxyl group. As disclosed in the patent identified above, the 3-keto-A structure of the A-ring of the steroid can be regenerated by treatment with alkali.

The term steroidal as used in this specification and claims relates to the basic cyclopentanopolyhydrophenanthrene tetranuclear structure possessing angular methyl groups at positions 10 and 13 which may or may not possess substitutents attached to the nuclear rings. The substituents contemplated on the steroidal 3-keto-A -diene starting materials are those which are non-interfering and would include the hydroxyl, acyloxy, methyl or other lower alkyl, methylene or other lower alkylene, fluoro or other halogen, or non-interfering keto and the substituents can be situated at positions in the steroidal molecule conventionally encountered in steroid products possessing pharmacological activities such as position 6, 7, 9, 11, 12, 15, 16 and 17. The starting materials may also contain additional double bonds and carboxyl groups as illustrated by 1.

The preferred starting materials can be represented by the following structural formula:

Ra wherein X represents (CH-COOR), (CH-CH OR or (0); R represents (H,H), (H,OH) or (O); and R represents H, a lower alkyl group, or halogen. In these formulas R represents hydrogen or a lower alkyl group, R represents the acyl radical of a hydrocarbon carboxylic acid of from 1 to 12 carbon atoms, and the designation 1 is a generic expression denoting a or 13 stereoconfiguration or mixtures thereof. Enamine formation, of course, eliminates stereoconfiguration ot R Upon reconstruction of the A -3,8 structure (i.e., removal of the enamine) the more stable u-configuration predominates.

A class of novel and useful compounds is afforded by the process of this invention as is illustrated in the following examples, namely the enamines of the foregoing class of compounds desired of lower aliphatic open chain secondary amines such as diethylamine, diisobutylamine, dipropylamine and the like, containing from 1 to 8 carbon atoms in each of the aliphatic groups. This novel class of compounds is represented by the following formula:

X I RF Y lower aliphatic lower aliphatic 11 in which the values of X, R, R R and R are as given above.

DETAILED DESCRIPTION OF THE INVENTION A typical starting steroidal 3-keto-A -diene is one havin g the following structure:

0 0 o C H;

A typical 3-enamine product has the following structure:

l l U lower al1phat1c\ /N lower aliphatic 3 been described [W. A. White and H. Weingarten, I.O.C. 32, 213 (1967)]. This prior reaction does not relate to the use of ketones having complex conjugated doublebondd tetranuclear systems such as I.

The amount of titanium tetrachloride used in this invention is preferably 0.55 to 0.70 mole equivalents relative to the 3-keto-A -steroidal diene.

The reaction can be carried out at room temperature though the temperature may vary from C. up to the boiling point of the reaction mixture. Lower temperatures are likely to work as long as the Solvent used does not freeze.

The secondary organic amine can be any such as dialiphatic amine, or N-aliphatic aromatic amine such as N-ethyl-aniline, or a heterocyclic amine such as the pyrrolidines or piperidines as disclosed in US. Pat. 2,781,343, or morpholine.

When titanium tetrachloride is used in excess of equivalent quantities, a considerable amount of enamine formation occurs as position C as well as at C giving III below, which reduces to IV as shown:

Such enamines as III are heretofore unknown and are useful in the preparation of prednisone by applying the reduction step using diisobutyl aluminum hydride or lithium aluminum hydride to produce the 17(20)-ene-21 01 structure Without reducing the ll-keto protected group. This permits direct oxidative hydroxylation to prednisolone by applying the teachings in US. Pat. No. 2,774,775, i.e., by reaction of the 21-acylated steroid with hydrogen peroxide and a small proportion of osmium tetroxide.

The 3,11-dimethyl dienamines of 3,11-diketo-4,l7(20)- pregnadiene 21-oic acid methyl ester find a similar use in the more direct preparation of cortisone by the steps of reducing the carboxyl group followed by the 21-esterification and then oxidative hydroxylation.

Formation of the 3,11-dimethyl dienamines as described above is aided by using a greater excess of titanium tetrachloride in the reaction, i.e., up to twice the molal ratio of the steroid used.

When using diethylamine in the process of this invention,'tl1e reaction seems to be more selective for exclusively forming the C diethylenamine corresponding to II, and for this reason it and other secondary amines of greater steric bulk than dimethylamine are preferred when the 3- monoenamine product is desired.

EXAMPLE A Experimental Preparation of dimethylenamine II (8644VVR48) Into a solution of 9.0 g. of dimethylamine in 130 ml. of benzene at 0 C., is slurried 7.1 g. of A -Favorskii methyl ester (I). To this mixture under nitrogen is slow- 1y added a solution of 2.1 g. of titanium tetrachloride in 10 ml. of benzene, keeping the reaction temperature below +5 C. The reaction is allowed to warm to room temperature and is stirred for two hours. Filtration of the precipitated titanium oxide and dimethylamine hydrochloride gives a light-yellow solution. Evaporation of the solvent and addition of methanol gives 2.5 g. of crystalline dimethylenamine II, which is analytically pure. M.P.: 170-174 C.

)t 222(21, 650);279 sh, (5,700) 330 mp sh, (62,750)

mam:

N.M.R. (CDClg): 60 (3H), 80 (3H), 159 (6H), 218 (3H), 295 (IH), 314 (1H), 340 (IH), 354 (IH), 389 cps. (1H).

The yield of enamine in the above example, based on material consumed, is in the range of 60-80%.

In place of the methyl ester above, the A -Favorskii ethyl, propyl or butyl esters can be used to produce, respectively, the corresponding 3-enamines.

In place of dimethylamine above, diethylamine, dipropylamine, diisobutylamine, propyl butyl amine or pyrrolidine, 2,4-dirnethylpyrrolidine and the like as disclosed in the analogous A compounds in US. Pat. 2,781,343 can be used, to produce, respectively, the corresponding 3-enamines.

In place of the starting material above, a compound having the skeletal structure of IV can be used, or its 21-acyl ester of a hydrocarbon carboxylic acid of from 1 to 12 carbon atoms (e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-etyhlbutyric hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, or other hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., cyclopropylideneacetic, cyclopentylformic, cyclopentylacetic, fl-cyclohexylpropionic, cyclohexylformic, cyclohexylacetic, ,B-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2, 3 or 4- methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, a-naphthoic, 3-methyl-a-naphthoic, phenylacetic, phenylpropionic, etc.).

EXAMPLE B Preparation of diethylenamine II (8644-VVR-69) EXAMPLE C Preparation of 3-diethylenamine of fifi-melhyl Favorskii methyl ester (8671-VVR-) COOCH;

COOCH;

CH1 ($11, CH; VI

A slurry of 3.0 g. of (V) in 40 ml. of dry benzene is cooled to 5 C. and 10 ml. diethylamine is added. A solution of 0.55 ml. titanium tetrachloride in 20 ml. benzene is added dropwise over /2 hour. After complete addition the reaction is allowed to warm to room temperature Where upon it is stirred for 2 hours. Then 0.2 ml. of H 0 in 2 ml. diethylamine is added with vigorous stirring and the precipitate of titanium oxide and amine hydrochloride filtered over sodium sulfate and washed with benzene. The filtrate is evaporated to dryness under vacuum giving an off-white solid which on trituration drolysis, and the resulting product converted to the known with methanol yields 2.26 g. (66%) of VI. useful product, estradiol, by 'known methods.

M.P.: 131-137" c. tent d NMR 3): 7 187, 219, 302, 341, 354, ewmvoun and 338 cps.

Calcd. (percent): 0, 76.55; H, 8.80; N, 3.31. Found COOCH (percent): C, 76.22; H, 8.70; N, 3.20. I

EXAMPLE D Preparation of 3-diethylenamine of 6u-methyl 0 Favorskii methyl ester (9418-MOP-1I3) oooona lower aliphatic lower/ O m aliphatic V i 2. The process which comprises reacting a compound of the following structural formula:

VII

6H3 vi To a solution of 6 ml. diethylamine in 15 m1. of dry benzene at 15 is slowly added 0.5 ml. of titanium tetrachloride in 10 ml. of benzene. After stirring 30 minutes, this titanium chloride-amine complex is then added over minutes to a solution of 1.8 g. of VII in 10 ml. of 30 dry methylene chloride at room temperature. After the 5 addition, this heterogeneous mixture is stirred at 5 for R;

3 hours after which 0.2 ml. of water in 1 ml. diethylamine is added with vigorous stirring. The resulting precipitate is filtered over sodium sulfate and washed with benzene. The filtrate is evaporated to dryness under vacuum, re- X=CH COOR, 2 1 0,

sulting in 2.0 g. (96%) of tan solid which is homogeneous R=hydrgen lower alkyl group, by NMR. Trituration with cold methanol gives 1.3 g. of R1=the acyl radlcal of a hydrocarbon carboxyhc n in which yellow solid identical in all respects with VI obtained of from 1 to 12 carbon atoms from V in Example C. 40 R2=(HH) (HOH) or R H, halogen or a lower alkyl group, EXAMPLE E =0: or ,3 or mixture of a and 8 Preparation of 3-diethylenamine 0 1A -andr0stadiene- Wlth secondary amine 1n the Presence of titanium 3,17-dione (8418-MOP-131) chllorlde- 3. The method of claim 2 1n which the starting mate- 0 O 49 rial is:

ooocrr, f 50 m EtlYI 0 VIII Et IX To a solution of 10 g. diethylamine in 15 ml. of dry benzene is added dropwise a solution of 0.5 ml. titanium tetrachloride in 10 m1. benzene. This solution of titanium tetrachloride amine complex is then added slowly to a mixture of 2.0 g. of VIII in 20 ml. of benzene and 10 ml. diethylamine maintained at 10 C. After stirring at 4, h method of claim 2 in which the Starting mate- -10 for 3 hours, 0.2 ml. of water in 2 ml. diethylamine ial i is added with vigorous stirring and the resulting precipitate filtered over sodium sulfate and washed with benzene. The filtrate is evaporated to dryness under vacuum giving 1.9 g. of solid IX.

NMR (COCl )=57 (3H), (3H), 63 tr. (6H), 187 (4H), 300 (111-1), 317 (IH), 362 (1H), 366 (IH), 334 cps. (1H) Mass spectrum=339 (m.+), 324, 311, 286, 284 m./c.

The product IX can be reduced by known methods for reducing steroid keto groups to the corresponding 17-hydroxyl compound by reaction with lithium aluminum hydride or diisobutyl aluminum hydride; the A -3-keto structure subsequently regenerated by base catalyzed hy- COOCH;

7 5. The method of claim 2 in which the starting mate- 6. The method of claim 2 in which the starting material is: rial is:

References Cited 0 UNITED STATES PATENTS 15 2,774,775 12/1956 Korrnan. 3,274,176 9/1966 Dub 260-2395 ELBERT L. ROBERTS, Primary Examiner 20 US. 01. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 5,629,298 Dated December 21, 1971 Patent No.

Inventor(s) Ver 1 an H. Van Rheenen It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 20, the formula should appear as shown below i nstead of as i n the patent lower al iphatic lower R8 aliphatic Column l l fie for "the A-actlon of I" read -the A-r'l ng Column 5, l l nes 59 and 61, for

"Example A structure of Experimental" "Experimental read Example A--.

Signed and sealed this 25th day of July 1972.

(SEAL) Attest:

EDWARD M.FLETCHE R,JR. ROBERT GOTTSCHALK Commissioner of Patents Attesting Officer USCOMM-DC 6O376-P59 U45. GOVERNMENT PRINTING OFFICE: I969 0-366-334 FORM Po'-1o50 (10-69) 

